Cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterases (PDE 1 to PDE 11). The PDE 7 selectively decomposes cAMP, and is characterized as an enzyme which is not inhibited by rolipram. Rolipram is a selective inhibitor of PDE 4, which decomposes cAMP similarly.
It is suggested that PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and is well known that activation of T-cell is concerned with the exacerbation of allergic diseases, inflammatory diseases or immunological diseases. These diseases are for example bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection reaction in transplantation, graft versus host disease (GVH disease), and restenosis after angioplasty [J. Allergy Clin. Immunol., 2000 November; 106(5 Suppl.): S221-6; Am. J. Respir. Crit. Care Med., 1996 February; 153(2): 629-32; Am. J. Respir. Crit. Care Med., 1999 November; 160(5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 Febuary; 30(2): 242-54; Hosp. Med., 1998 July; 59(7): 530-3; Int. Arch. Allergy Immunol., 1998 March; 115(3): 179-90; J. Immunol., 1991 Feb. 15; 146(4): 1169-74; Osteoarthritis Cartilage, 1999 July; 7(4): 401-2; Rheum. Dis. Clin. North Am., 2001 May; 27(2): 317-34; J. Autoimmun., 2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000 Febuary; 2(1): 24-31; Trends Immunol., 2001 January; 22(1): 21-6; Curr. Opin. Immunol., 2000 August; 12(4): 403-8; Diabetes Care, 2001 September; 24(9): 1661-7; J. Neuroimmunol., 2000 Nov. 1; 111(1-2): 224-8; Curr. Opin. Immunol., 1997 December; 9(6):793-9; JAMA, 1999 Sep. 15; 282(11):1076-82; Semin. Cancer Biol., 1996 April; 7(2):57-64; J. Interferon Cytokine Res., 2001 April; 21(4):219-21].
Therefore, it is considered that a compound having PDE 7 inhibiting effect is useful for treating various kinds of diseases such as allergic diseases, inflammatory diseases or immunological diseases concerned with T cells.
There has been proposed that many compounds selectively inhibit PDE 7. There can be mentioned the examples such as imidazopyridine derivatives (Patent Document 1), dihydropurine derivatives (Patent Document 2), pyrrole derivatives (Patent Document 3), benzothiopyranoimidazolone derivatives (Patent Document 4), heterocyclic compounds (Patent Document 5; Patent Document 6), quinazoline and pyridopyrimidine derivatives (Patent Document 7), spiro tricyclic compounds (Patent Document 8), thiazole and oxathiazole derivatives (Patent Document 9), sulfonamide derivatives (Patent Document 10), heterobiarylsulfonamide derivatives (Patent Document 11), dihydroisoquinoline derivatives (Patent Document 12), guanine derivatives (Non-Patent Document 1), benzothiadiazine derivatives and benzothienothiadiazine derivatives (Non-Patent Document 2, and Non-Patent Document 3). However, no curative medicines having PDE 7 inhibiting effect as main pharmacological mechanism have developed up to now.
Though some compounds having thienopyrazole skeleton have been known (Patent Documents 13-24; Non-Patent Documents 4-8), there is no suggestion that these compounds have PDE 7 inhibiting effect. Further, the method for producing the thienopyrazole derivatives of the present invention has been reported (Non-Patent Documents 9-11); however, the substituents on the thienopyrazole skeleton are different from those of the present invention.    Patent Document 1: International Patent Publication WO 01/34,601    Patent Document 2: International Patent Publication WO 00/68,203    Patent Document 3: International Patent Publication WO 01/32,618    Patent Document 4: DE Patent 19,950,647    Patent Document 5: International Patent Publications WO 02/88,080    Patent Document 6: International Patent Publications WO 02/87,513    Patent Document 7: International Patent Publication WO 02/102,315    Patent Document 8: International Patent Publication WO 02/74,754    Patent Document 9: International Patent Publication WO 02/28,847    Patent Document 10: International Patent Publication WO 01/98,274    Patent Document 11: International Patent Publication WO 01/74,786    Patent Document 12: International Patent Publication WO 02/40,450    Patent Document 13: International Patent Publication WO 02/100,403    Patent Document 14: International Patent Publication WO 02/79,146    Patent Document 15: International Patent Publication WO 02/66,469    Patent Document 16: International Patent Publication WO 01/90,101    Patent Document 17: U.S. Pat. No. 6,022,307    Patent Document 18: International Patent Publication WO 03/024,962    Patent Document 19: International Patent Publication WO 03/029,245    Patent Document 20: International Patent Publication WO 03/040,096    Patent Document 21: International Patent Publication WO 03/097,617    Patent Document 22: International Patent Publication WO 03/099,821    Patent Document 23: International Patent Publication WO 97/27,200    Patent Document 24: U.S. Pat. No. 3,649,641    Non-Patent Document 1: Bioorg. Med. Chem. Lett., 11(2001), 1081    Non-Patent Document 2: J. Med. Chem., 43(2000), 683    Non-Patent Document 3: Eur. J. Med. Chem., 36(2001), 333    Non-Patent Document 4: Russ. J. Org. Chem., 39(2003), 893    Non-Patent Document 5: Aknos Consulting and Solutions GmbH Co., Catalog: Akos samples     Non-Patent Document 6: Phosphorus, sulfur and silicon and related Elements, 157 (2000), 107    Non-Patent Document 7: Zhurnal Organisheskoi Khimii., 9(1973), 2416    Non-Patent Document 8: Zhurnal Organisheskoi Khimii., 5(1969), 1498    Non-Patent Document 9: Phosphorus, sulfur and silicon and related Elements, 157 (2000), 107    Non-Patent Document 10: Chinese Chemical Letters, 10(3), (1999). 189    Non-Patent Document 11: Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 35B(7), (1996), 715